This study is a randomized, double-blind, placebo-controlled, crossover trial comparing the effects of pioglitazone versus placebo in 26 subjects with severe, refractory asthma. The objective of this study will be to assess the efficacy of pioglitazone hydrochloride for patients with severe, refractory asthma. The primary objective is to assess whether pioglitazone hydrochloride can improve quality of life. The secondary objectives are to assess the efficacy of pioglitazone hydrochloride on indices of airway inflammation, airflow obstruction, airway hyperreactivity, and asthma symptoms. We will screen up to 300 subjects to obtain 26 completers. Study participants must be between the ages of 18 and 75 and can be male or female. Patients will be counseled regarding alternative treatment options. Patients will be screened to assess whether they meet the inclusion and exclusion criteria. The following studies will be performed: history and physical examination (including age of onset, BMI, exacerbation history and use of OTC compounds herbs/supplements), breathing tests (pulmonary function tests), chest x-ray, electrocardiogram (heart tracing), echocardiogram (uses sound waves to test the function of the heart), blood tests, and pregnancy test. Subjects will be classified as having asthma on the basis of the following factors. First, they must have had occasional wheezing. Second, we will show that they have abnormal lung function and have had airway hyperreactivity at some point in their past. They will be asked to perform breathing tests before and after they breathe a medication called albuterol, which should relax their lung tubes if they have asthma. Albuterol is used to treat asthma and should improve the amount of gas they can breathe out. They must have either a significant improvement in lung function following an albuterol treatment, or an abnormal response to methacholine testing, at some point in their life, to be included in the study. Albuterol inhalation is a routine test that is used to evaluate patients with lung disease. Subjects who fulfill the inclusion and exclusion criteria will be invited to participate in the study. The study will be divided into 5 time periods; a 4-week run-in period (Phase 1), two 16-week treatment periods (Phases 2 and 4) separated by an 8 week washout (Phase 3), which includes a second 4 week run in period (Phase 3a), and a 4-week follow-up period (Phase 5), for a total study duration of 48 weeks. We anticipate 2 outpatient visits will be required to complete the screening assessment. Therefore, the study will include 14 outpatient visits. Phase I and III Run-in Phase: Prior to being randomized to receive pioglitazone or placebo, patients will participate in a 4-week run-in phase, during which time baseline symptoms will be documented. Subjects must have stable asthma during the run-in period, which will be defined as: absence of unscheduled health care visit for asthma care and no change in asthma maintenance medications. Study subjects must also comply with home monitoring of asthma symptoms and peak expiratory flow during the run-in period to be eligible to proceed to the treatment phase. Study subjects who are unable to monitor daily asthma symptoms and peak expiratory flow rates will not be randomized to receive pioglitazone or placebo. Only at the completion of the first run-in period (week 0), in addition to the testing described for the Treatment Periods (Phases 2 and 4), allergy skin testing and methacholine bronchoprovocation testing will be performed. An investigator will be present for aeroallergen skin testing and methacholine bronchoprovocation testing. Phase II and IV - Treatment Phase: Subjects will be randomized by the NIH Clinical Center pharmacy to receive either pioglitazone or a placebo that will match the active treatment. Subjects will receive 30 mg daily ofpioglitazone for the first 2 weeks of each treatment phase and then be escalated to 45 mg daily of pioglitazone or placebo for weeks 3 through 16. Subjects will be monitored as outpatients on a monthly basis for weeks 0 - 16 (+/- 10 days) and weeks 24 40 (+/- 10 days). Studies to be performed at each visit will include: history and physical examination (including age of onset, BMI, exacerbation history); blood draw (CBC including differential including absolute and percentage eosinophils and neutrophils, electrolytes including BUN, creatinine, LFTs including transaminases, bilirubin, alkaline phosphatase, IgE, CPK, pro-BNP, research weeks 0, 16, 24, 40, and Vitamin D, 25-hydroxycholecalciferol level Week 0; if abnormal, the subject and their primary care physician will be notified); spirometry (pre- and post-bronchodilator) Note: Full PFTs (with pre/post BD) will be performed in place of spirometry at the beginning and end of each of the Treatment Periods (Weeks 0, 16, 24, 40); weight and body mass index; asthma control score; Asthma Quality of Life Score; measurement of exhaled nitric oxide; and pregnancy test. Subjects will keep a log at home of their asthma symptom score, inhaled b-agonist use, nocturnal awakenings and need for unscheduled medical care for asthma symptoms (urgent physician or emergency department visit, hospitalization). The daily morning and evening PEF and FEV1 will be recorded electronically. Study participants will be provided with an electronic peak flow meter for home monitoring of PEF and FEV1.. Phase III Wash-out Period: During this period, no study medications will be administered. At week 20, the beginning of the second Run-In Period (Phase 3a), evaluation will be the same as the evaluation and testing during the treatment periods. Phase V Follow-up Evaluation Period: Subjects will undergo a follow-up evaluation, with testing as described for phases II and IV, at 4 weeks after the completion of the 2nd treatment phase, with the exception of pregnancy test and research blood (week 44). Participants will also be enrolled in a collaborative study with the NIH Center for Human Immunology to assess the effects of pioglitazone on immune cell function. This study showed that the PPAR-gamma agonist, pioglitazone, was associated with significant side effects and did not improve the primary outcome measure of the Juniper Asthma Quality of Life Questionnaire (AQLQ) score in severe asthmatics. We conclude that no further studies should be performed with pioglitazone for severe asthma. The results of this study were published in 2017 in the Journal of Allergy and Clinical Immunology (J Allergy Clinical Immunol 2017. Dec; 140(6):1716-1718. don 10.1016/j.jaci.2017.05.033). This study remains open for data and specimen analysis. No additional subjects will be accrued to this study.